Genetic and Pharmacological Discovery for Alzheimer’s Disease Using Caenorhabditis elegans

Abstract

The societal burden presented by Alzheimer's disease warrants both innovative and expedient means by which its underlying molecular causes can be both identified and mechanistically exploited to discern novel therapeutic targets and strategies. The conserved characteristics, defined neuroanatomy, and advanced technological application of Caenorhabditis elegans render this metazoan an unmatched tool for probing neurotoxic factors. In addition, its short lifespan and importance in the field of aging make it an ideal organism for modeling age-related neurodegenerative disease. As such, this nematode system has demonstrated its value in predicting functional modifiers of human neurodegenerative disorders. Here, we review how C. elegans has been utilized to model Alzheimer's disease. Specifically, we present how the causative neurotoxic peptides, amyloid-β and tau, contribute to disease-like neurodegeneration in C. elegans and how they translate to human disease. Furthermore, we describe how a variety of transgenic animal strains, each with distinct utility, have been used to identify both genetic and pharmacological modifiers of toxicity in C. elegans. As technological advances improve the prospects for intervention, the rapidity, unparalleled accuracy, and scale that C. elegans offers researchers for defining functional modifiers of neurodegeneration should speed the discovery of improved therapies for Alzheimer's disease.

Modeling neurodegeneration in Caenorhabditis elegans

“…The worm APL-1 protein is an ortholog of the human amyloid beta precursor-like proteins 1 and 2 (APLP1 and APLP2), and has 71% sequence similarity to the intracellular domain of APP, but completely lacks an Aβ domain. Thus, AD modeling in C. elegans has primarily focused on the transgenic expression of mature human Aβ and tau ( Griffin et al, 2017 ). Nevertheless, single-copy insertion and expression of human APP results in neurodegeneration and neurobehavioral dysfunction in C. elegans ( Yi et al, 2017 ) .…”

The Role of Ca2+ Signaling in Aging and Neurodegeneration: Insights from Caenorhabditis elegans Models

“…The resulting transgenic worms suffered paralysis, and characteristic Aβ deposits were observed in the muscles. Several worm models with either muscle or neuronal Aβ 1-42 or Aβ 3-42 expression have since been made, and they have also been used to investigate the neuroprotective effect of several compounds [7,[9][10][11][12][13][14].…”

Tumour travel tours – Why circulating cancer cells value company

“…Brenner's first study reported hundreds of mutants and related genes [13]. Since then, C. elegans has become an evergreen model organism for a broad scientific community, and despite the latest trend to go as human-like as possible for some studies (like miniature brains in a dish [14]), the worm has never lost its pertinence for the understanding of both normal ontogenesis and various human pathologies, including neurodegenerative diseases [15].…”